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ERJ Express. Published on March 18, 2015 as doi: 10.1183/09031936.

00119114

STATE OF THE ART
IN PRESS | CORRECTED PROOF

State of the art review: management of
bronchiectasis in adults
James D. Chalmers1, Stefano Aliberti2 and Francesco Blasi3

Affiliations:
1
Tayside Respiratory Research Group, University of Dundee, Dundee, UK.
2
Department of Health Science, University of Milan Bicocca, Clinica Pneumologica, Monza, Italy.
3
Department of Pathophysiology and Transplantation, University of Milan, IRCCS Fondazione Ca’ Granda
Ospedale Maggiore Policlinico, Milan, Italy.

Correspondence: Francesco Blasi, Department of Pathophysiology and Transplantation, University of Milan,
IRCCS Fondazione Ca’ Granda Ospedale Maggiore Policlinico, Via F. Sforza 35, Milan, Italy.
E-mail: francesco.blasi@unimi.it

ABSTRACT Formerly regarded as a rare disease, bronchiectasis is now increasingly recognised and a
renewed interest in the condition is stimulating drug development and clinical research. Bronchiectasis
represents the final common pathway of a number of infectious, genetic, autoimmune, developmental and
allergic disorders and is highly heterogeneous in its aetiology, impact and prognosis.
The goals of therapy should be: to improve airway mucus clearance through physiotherapy with or
without adjunctive therapies; to suppress, eradicate and prevent airway bacterial colonisation; to reduce
airway inflammation; and to improve physical functioning and quality of life.
Fortunately, an increasing body of evidence supports interventions in bronchiectasis. The field has
benefited greatly from the introduction of evidence-based guidelines in some European countries and
randomised controlled trials have now demonstrated the benefit of long-term macrolide therapy, with
accumulating evidence for inhaled therapies, physiotherapy and pulmonary rehabilitation.
This review provides a critical update on the management of bronchiectasis focussing on emerging
evidence and recent randomised controlled trials.

@ERSpublications
Bronchiectasis is a rapidly developing field: review of recent RCTs and progress towards
developing new therapies http://ow.ly/JXGWM

Received: June 29 2014 | Accepted after revision: Jan 06 2015
Conflict of interest: Disclosures can be found alongside the online version of this article at erj.ersjournals.com
Copyright ©ERS 2015

Eur Respir J 2015; in press | DOI: 10.1183/09031936.00119114 1
Copyright 2015 by the European Respiratory Society.

it is clear. 26]. “macrolide”. Work over several decades has implicate neutrophil elastase in this process.8–3 per patient per year. Since neutrophils from bronchiectasis patients are believed to be normal prior to their arrival in the airway.6–31.4% over 2 years follow-up [7]. but also organisms previously not recognised by culture-based studies like Veilonella sp. GOEMINNE et al. In a prospective cohort analysis of 245 patients in secondary care in Belgium. The effects of elastase on airway epithelial cells includes slowing of ciliary beat frequency and promotion of mucus hypersecretion [17. Georges Respiratory Questionnaire (SGRQ) in 1994. is associated with worse lung 2 DOI: 10. The search was supplemented by reviewing treatment options identified in the British Thoracic Society (BTS) bronchiectasis guidelines [2] and Spanish SEPAR bronchiectasis guidelines [3] and conducting updated searches for additional studies. focussing on existing and developing therapies.. 18] while impairment of opsonophagocytosis occurs at multiple levels. 30% of the cohort died over this period. Pseudomonas aeruginosa and Moraxella sp. LOEBINGER et al. in part because of the lack of representative experimental models.9% per year . The purpose of this article is to provide a state-of-the-art review on the rapidly developing field of bronchiectasis.1183/09031936. [4] reported an increase in hospitalisations for bronchiectasis in Germany between 2005 and 2011 with an average increase in the age-adjusted rate of 2. Other mechanisms of immune dysfunction include failure of clearance of apoptotic cells and T cell infiltration. The overall prevalence is not precisely known and recent estimates of 52/100 000 from the USA are likely to be an underestimate [6]. [10] found that 58% of deaths were respiratory related and 16% were cardiovascular. “anti-inflammatory”. “bronchodilators” and “mucolytics”. “antibiotics”. Alpha defensins released from neutrophil granules also suppress phagocytic responses [21]. with around one-quarter dying from cardiovascular diseases [8]. much more work is needed to unravel the complexities of the host response in bronchiectasis. at least in secondary care bronchiectasis cohorts. Similar data have been reported from the USA [5]. CHALMERS ET AL. The pathophysiology of bronchiectasis and the goals of treatment Our understanding of the pathophysiology of bronchiectasis is limited. Therefore. resulting in more clinical research and the development of new treatments [2]. “inhaled”. Prevotella sp.. Nevertheless. Studies in bronchiectasis reveal colonisation with familiar pathogens such as Haemophilus sp. A recent multicentre European study of 1310 patients with bronchiectasis identified an annual exacerbation frequency of 1. International data show an increase in the prevalence of bronchiectasis over recent years. These patients were followed up for 14 years.. The impact on healthcare systems is substantial. it is likely that the airway inflammatory milieu itself impairs bacterial clearance [15. through cleavage of opsonins from the bacterial surface and cleavage of the neutrophil surface receptors FcγRIIIb and CD35 [19. Airway inflammation in bronchiectasis is dominated by neutrophils. driven by high concentrations of neutrophil chemo-attractants such as interleukin-8 (CXCL-8) and leukotriene B4 [11–14]. Such technologies have clearly disproven the previous teaching that the healthy airway is sterile. and Neisseria sp. and clinically by a syndrome of cough. 16]. with a hospitalisation rate of 26. emphasising the need for high-quality specialised care for these patients.D. Clinical translation to date suggests that loss of diversity. Search strategy The authors conducted a systematic review of the PubMed database up to November 2014 using the search term “bronchiectasis” with “treatment”. Bronchiectasis has a clear attributable mortality. recent years have seen renewed interest in the disease. Airway bacterial colonisation occurs because of impaired mucociliary clearance and because of failure of neutrophil opsonophagocytic killing. henceforth referred to simply as bronchiectasis) is characterised radiologically by permanent dilation of the bronchi.00119114 .MANAGEMENT OF BRONCHIECTASIS IN ADULTS | J. 70% of deaths were due to respiratory causes. In Europe. with recent evidence pointing to an important role of Th17 cells [22. sputum production and recurrent respiratory infections [1]. How common is bronchiectasis? The prevalence of bronchiectasis is not precisely known and has been historically underestimated. [9] provided long-term data on mortality by following up a cohort of patients first recruited for the validation of the St. that patients experience a high rate of exacerbations. Significant recent advances in our understanding of bronchiectasis have arisen through 16S rRNA sequencing technologies which allow a comprehensive analysis of polymicrobial bacterial communities in the lung [24]. 50% of patients died from respiratory causes. with dominance of one or a few species. Having been previous regarded as a neglected “orphan” disease. 23]. New treatment strategies were identified through searches of clinical trials registries. Introduction Bronchiectasis not due to cystic fibrosis (“non-CF bronchiectasis”. hospital admissions and attributable mortality. “physiotherapy”. representing a greater than two-fold increase over the expected mortality for the healthy population. 20]. [25. RINGSHAUSEN et al. In the largest cohort study reported to date.

Overall these studies are consistent with data from culture based studies. aeruginosa.D. Vaccination against influenza and pneumococcal disease is also recommended as for other chronic respiratory disorders although there are no specific data in bronchiectasis about its impact [2].1183/09031936. and requires further study. Successful stabilisation of a patient with plasma exchange demonstrated the potential of this finding to change clinical practice [29]. As with other respiratory diseases. aeruginosa colonisation had these antibodies and they correlated with worse lung function and disease severity. common variable immunodeficiency [31]. DOI: 10. function and more exacerbations.00119114 3 . the pathophysiology of bronchiectasis is still best understood in terms of the vicious cycle hypothesis first proposed by COLE [14]. Since such responses are not necessarily unique to P. Despite these advances. and that loss of diversity may occur during exacerbations [25–28]. aeruginosa can induce the formation of O-antigen specific immunoglobulin (Ig) G2 antibodies which then protect the bacteria from complement-mediated killing [29]. particularly mannose-binding lectin deficiency have now been associated with more severe bronchiectasis in CF [30]. airway inflammation and airway structural damage. Additional defects in the complement system. CHALMERS ET AL. the goals of therapy should be to halt or reverse these processes and thereby “break the cycle”. Bacteria have their own methods of evading airway clearance. General management 7–18% of patients with bronchiectasis are current smokers. A significant proportion of patients with severe bronchiectasis and P. Bronchodilators Pulmonary rehabilitation management of co-morbidities Structural lung damage and airflow obstruction Failure of mucus clearance Bacterial colonisation Physiotherapy Macrolide therapy Airway adjuncts Inhaled antibiotics Pseudomonas aeruginosa eradication Airway inflammation Macrolide therapy Inhaled corticosteroids FIGURE 1 Current therapies for bronchiectasis displayed according to Cole’s vicious cycle hypothesis. MANAGEMENT OF BRONCHIECTASIS IN ADULTS | J.or culture-based means and high bacterial loads of “classical” bronchiectasis pathogens being associated with higher neutrophilic inflammation and more exacerbations [28]. An important recent study identified that P. Since progression of the disease is linked to failed mucus clearance. based on large cohort studies to date [7]. with Pseudomonas aeruginosa dominance being associated with worse lung function and more exacerbations whether by molecular. The following sections discuss these therapeutic approaches in detail [2]. patients with bronchiectasis should be encouraged to stop smoking. this finding could have even broader implications. airway bacterial colonisation. primary ciliary dyskinesia [32] and in a general population of patients with bronchiectasis [33]. Figure 1 shows a modification of the original vicious cycle indicating the treatment options for each component [14]. Pathological processes are shown in boxes with the current recommended therapies next to them.

Identifying and treating the underlying cause Bronchiectasis represents the final common pathway of a number of diseases. [48] studied 95 patients with bronchiectasis. In a recent randomised controlled trial by LEE et al. [46] performed a randomised crossover trial in 20 patients not currently practicing chest clearance. in the authors’ opinion.5 m) . At the end of treatment.1183/09031936. IgG and IgE). α1 antitrypsin. Immunoglobulin replacement. aeruginosa and Staphylococcus aureus isolation. 3]. in secondary care populations studied to date 35% [34]. IgM. Despite extensive testing. 45]. 43% [35] and 53% [36] of patients may have no identifiable cause. Bronchiectasis also appears relatively common in patients meeting the diagnostic criteria for asthma [42]. MURRAY et al. A subsequent pilot randomised controlled trial showed improvements in LCQ and SGRQ sustained to 20 weeks after treatment [49]. The evidence for physiotherapy interventions in bronchiectasis is weak. testing to exclude ABPA (specific IgE to Aspergillus. ONG et al. The poor state of evidence in this area. treatment for NTM and of CF all represent opportunities to specifically treat the underlying cause and so systematic testing of all patients is recommended in consensus guidelines [2. is exercise [48]. with bronchiectasis reported in up to 50% of patients with moderate-to-severe COPD [40. CHALMERS ET AL. [50]. The effect on quality of life (7. steroids and anti-fungals for ABPA. Airway clearance Most physicians recommend mucus clearance as the mainstay of therapy in bronchiectasis. even if for very mild patients. Less data on aetiology is available outside the UK. is illustrated by the associated Cochrane review [47]). Testing for CF (sweat test and/or screening for common CF mutations) is recommended for patients aged <40 years or with recurrent P.D. Focal bronchiectasis may be associated with bronchial obstruction. There is little evidence so far that they represent a distinct phenotype from idiopathic bronchiectasis and some cases may represent recall bias [35]. IgG to Aspergillus and eosinophil count) and specific antibody responses to pneumococcal and Haemophilus vaccination [2]. They concluded that airway clearance techniques were safe and that the limited data suggested improvements in sputum expectoration. Consensus guidelines recommend that all patients with bronchiectasis receive some instruction in physiotherapy. they have clearly demonstrated the benefits of rehabilitation are at least as great in bronchiectasis as in COPD [48]. 4 DOI: 10. taking into account that simple and quicker techniques will encourage patient adherence [44. improved dyspnoea and a reduced time to the next exacerbation and total number of exacerbations over 12 months (median (IQR) 1 (1–3) versus 2 (1–3). in the author’s opinion. cough improved as measure by the Leicester Cough Questionnaire (LCQ). an 8-week supervised exercise training schedule that include airway-clearance techniques was compared with standard care .00119114 . London. There are a wide range of techniques and. and a report by MCSHANE et al. Post-infectious bronchiectasis is often used as a diagnostic label for patients with a history of severe or childhood respiratory infections. UK) oscillatory positive expiratory pressure device for 3 months with no chest physiotherapy for 3 months. but data from Italy and Belgium suggested a spectrum similar to the UK with perhaps fewer patients with allergic bronchopulmonary aspergillosis (ABPA) and more with chronic obstructive pulmonary disease (COPD) [7]. and measurement of autoantibodies are also suggested. however. or upper lobe predominant disease irrespective of age [2]. they only perform physiotherapy during exacerbations. This review found the body of evidence for physiotherapy in bronchiectasis constituted five trials with 51 participants [47]. ciliary function tests). affecting 20–30% of patients [7. Additional testing is recommended in specific circumstances (bronchoscopy.8 points on the SGRQ) was excellent and well above the clinically important difference of 4 points [46]. demonstrating a mean improvement in 6-min walk distance of 53 m which was sustained to 12 months (difference at 12 months 20. In a retrospective study. and compared use of the Acapella® (Smiths Medical. reduced hyperinflation and improved health-related quality of life in stable patients. Sputum culture to exclude NTM. 43 patients were randomised to exercise training and 43 to standard care.MANAGEMENT OF BRONCHIECTASIS IN ADULTS | J. patients in the exercise group had an increase in 62 m in their incremental shuttle walk distance. many of which require specific treatment. the chosen technique should be tailored to the patient preference. however. One of the most effective forms of chest physiotherapy. Gastro-oesophageal reflux frequently co-exists with bronchiectasis and has been suggested as an aetiological factor in some cases [43]. Pulmonary rehabilitation is recommended for patients with bronchiectasis and although studies to date have been small. Data from the USA clearly demonstrate more bronchiectasis due to non-tuberculous Mycobacteria (NTM) in some centres [38]. At completion of the study. [39] of 106 patients identified an aetiology in 93% of cases. with increases in spontaneous 24-h sputum volume and exercise capacity. 34–37]. The BTS guidelines recommend testing for underlying causes including measurement of immunoglobulins (IgA. COPD appears to be a very common aetiology. 41].

54¶ 1. requiring two exacerbations in the previous year.3 67. All three trials used the frequency of exacerbations as the primary outcome. This study clearly demonstrates a benefit of exercise to patients with bronchiectasis.17 −1.1 64.34 (mean) Not reported Not reported 4.9 −4.1 36.7 40.12 −12. Among secondary endpoints there was an increase in time to next exacerbation and a small improvement in SGRQ with mannitol treatment [56]. A summary of these three trials in shown in table 1. but there are no controlled trials to demonstrate if this practice is beneficial [54].10 1.001 compared with placebo group. but most of the benefits were not sustained to 6 or 12 months suggesting this kind of intervention needs to be continuous to achieve long-term benefits [50]. A large trial of hypertonic saline is needed. compared with CF-associated bronchiectasis.3).92 −5.1 66. but used different macrolides. #: p<0. Oral antibiotics and anti-inflammatories Macrolides have been widely used for bronchiectasis for many years but there was a lack of evidence until three “game-changing” studies in 2012/2013.5 61.0 (median) SGRQ 36.9 82.6 59. ¶: p<0. with a rate ratio for exacerbations of 0.93 (mean) 3. Therefore a further trial was conducted focussing on exacerbations. FEV1 between 40 and 85% predicted and a baseline SGRQ score of ⩾30 points [56]. MANAGEMENT OF BRONCHIECTASIS IN ADULTS | J.03# Change in SGRQ from baseline −1.05 compared with placebo. The population was tightly defined.0 (median) 5. CHALMERS ET AL.78–1.08.6# −0. This study randomised 233 patients to 400 mg inhaled mannitol or control mannitol for 52 weeks [56]. are widely used as evidenced by the BTS audit. despite two large trials the role of mannitol in bronchiectasis treatment remains unclear.9 Baseline data FEV1 % predicted at baseline 67. and required patients in addition to a computed tomography diagnosis of TABLE 1 Summary of three double blind randomised controlled trials of macrolides in non-CF bronchiectasis EMBRACE: New Zealand BLESS: Australia BAT: Netherlands Placebo Azithromycin Placebo Erythromycin Placebo Azithromycin 500 mg three 400 mg twice 250 mg once times per week daily daily Subjects n 70 71 58 59 40 43 Male % 29 32 43 36 30 42 Mean age years 59. different doses and had slightly difference inclusion and exclusion criteria [57–59]. reducing FEV1 .3 g) with no significant difference in quality of life using the SGRQ [55]. [53] in bronchiectasis.2 40.01). Therefore. which now provide robust evidence to support their use [57–59]. p=0.27# 1.1 70. Inhaled dry powder mannitol has been the subject of two recent phase 3 randomised controlled trials [55] The first study included 231 patients on 320 mg mannitol twice daily or placebo (an inactive dose of mannitol) twice daily for 12 weeks followed by open label extension for 52 weeks.18# Total exacerbations in 12 months 178 109 114 76 78 39 during trial n Mean exacerbation rate during 2.6 31. George’s Respiratory Questionnaire. 52].9 63. Hypertonic saline may improve forced expiratory volume in 1 s (FEV1) when used in combination with chest physiotherapy but a recent trial could not clearly establish it was superior to 0.9% saline [51.1183/09031936. The study failed to meet its primary end-point.3 −3. The mucolytics. DOI: 10.7 77. such as nebulised hypertonic saline solution.92 (95% CI 0.9 38. The primary outcome was the rate of pulmonary exacerbations over 1 year.00119114 5 . Inhaled hyperosmolar agents and mucolytics A variety of agents.7 Exacerbation rate pre-trial 3. Recombinant DNase is effective in CF but has been shown to be potentially harmful in a randomised controlled trial by O’DONNELL et al. It was not clear if the differences in sputum weight were due to higher antibiotic use in the placebo group. have been developed to help patients to clear airway secretions. The Bronchiectasis and Long Term Azithromycin Treatment (BAT) trial used azithromycin 250 mg daily. The study found an increased sputum weight in favour of mannitol (mean 4.0 60.54 1.91¶ trial (per patient) SGRQ: St. for example carbocisteine and N-acetylcysteine.0 −1.D. It is therefore not advised for use in this group of patients. mannitol and mucolytic agents. and highlights the different pathophysiology in bronchiectasis.6 Outcomes Change in FEV1 with treatment −0. p=0.97 1.04 0 −4.95 0.

00119114 . the absence of high-quality evidence means that decisions to use or discontinue combined ICS and long-acting β-adrenoceptor agonist (LABA) in people with bronchiectasis may need to take account of the presence or absence of co-existing airway hyper-responsiveness and 6 DOI: 10. The Bronchiectasis and Low Dose Erythromycin Study (BLESS) trial used Erythromycin ethylsuccinate 400 mg twice daily and required two exacerbations in the previous year [58]. There is a lack of evidence for alternative long-term oral antibiotics. Additional concerns over macrolides include the possibility of inducing resistance in NTM.88 to −9. macrolides have anti-inflammatory effects including inhibition of inflammatory cell migration.1183/09031936. for example.D. Inhaled corticosteroids and bronchodilators The role of inhaled corticosteroids (ICS) in bronchiectasis is less clear. Further research needs to explore the best dosage and schedule for macrolide therapy with a clear aim of optimising benefits and reducing adverse events [65]. How macrolides achieve their beneficial effects is unclear. All these trials have shown a significant reduction in exacerbation frequency compared to placebo during the treatment period as shown in table 1. aeruginosa [2].89). 66].39 (95% CI −0. but the key question is in which patients they should now be used. Alongside their antimicrobial effects. aeruginosa [60].35). hepatotoxicity and decreased hearing [62]. macrolides are most frequently used in patients with three or more exacerbations per year. bronchiectasis to have had three exacerbations in the previous year and a positive sputum culture for bacteria [57]. Macrolides should be avoided in patients with a prolonged QT interval. A recent secondary analysis of the BLESS trial has suggested that erythromycin therapy was associated with the emergence. Azithromycin was associated with increased gastrointestinal side effects in the BAT trial. reduce inflammatory markers in sputum and improve quality of life [69]. cytokine secretion and possible attenuation of the production of reactive oxygen species [63. with small changes in FEV1 which are unlikely to be of clinical significance. they have not shown any significant improvement in lung function. an overall reduction in SGRQ compared with placebo of −5. given that the EMBRACE trial showed benefit in patients with one or more exacerbations per year. The combination group experienced improved dyspnoea. the combination of inhaled formoterol plus budesonide was compared with inhaled budesonide alone [70]. required only one exacerbation in the previous year and used Azithromycin 500 mg three times per week [59]. Improvements were also observed in the SGRQ. coughing and health-related quality of life without alteration in sputum pathogens or an increase in adverse effects [70]. 64] Other mechanisms that have been proposed to explain macrolide benefit include reduction of biofilms surrounding virulent Gram-negative organisms such as P. Agents used frequently in clinic practice include β-lactams (amoxicillin or co-amoxiclav) and tetracyclines [2]. Macrolides are therefore effective. and controlled trials are needed. using molecular techniques. CHALMERS ET AL. small but significant improvements in dyspnoea and sputum volume and a clinically insignificant improvement in FEV1 of 20 mL. In clinical practice. BTS guidelines recommend consideration of long-term oral antibiotics for patients with ⩾3 exacerbations per year or those chronically colonised with P. No patients became colonised with P. or exacerbation frequency. although erythromycin appeared to be better tolerated in BLESS [58] There have been other concerns regarding macrolides including an increased incidence of cardiovascular events although no cardiovascular complications were observed in these small RCT’s [61].MANAGEMENT OF BRONCHIECTASIS IN ADULTS | J. while the Azithromycin for Prevention of Exacerbations in non-CF Bronchiectasis (EMBRACE) trial conducted in New Zealand. Several meta-analyses of the evidence for macrolides in bronchiectasis have recently been reported. demonstrated a pooled effect of macrolides that equated to a reduction of 1 exacerbation per patient per year (95% CI 0. of P. The main concern of macrolide therapy is a marked increase in macrolide resistance in oropharyngeal and other bacteria. in patients with P. However. The authors recommend warning patients regarding hearing loss and to perform electrocardiogram and sputum culture for NTM prior to commencement of macrolide therapy. They have an established role in asthma and COPD. these recommendations may change. These guidelines were written before the publication of the three recent trials and. and are used in patients with bronchiectasis complicating these two disorders [68]. Some studies have shown that regular high-dose inhaled steroids reduce 24-h sputum volume. As pointed out in a recent Cochrane review. The treatment period was 12 months in BAT and BLESS and 6 months in EMBRACE. aeruginosa and also in patients with less frequent exacerbations who continue to have significant impairment of quality of life despite standard treatment. aeruginosa and promotion of gastric emptying that may reduce potential for acid reflux [65. WU et al. In a small randomised controlled trial in bronchiectasis patients with chronic airflow limitation (but not a primary diagnosis of asthma or COPD). The BAT trial showed macrolide resistance of 88% in the treatment group compared to 26% on placebo [59].67–1. [67]. aeruginosa by culture and so the clinical importance of this finding is not clear.

9) log10 cfu·mL−1 versus 7. [81]. gentamicin and colomycin.5 points.0–5. These adverse effects include the recently noted increase in pneumonia risk in COPD patients [73]. UK) device. p=0. The I-Neb device allows the monitoring of compliance and. sputum volume and improvements in inflammatory markers [78–80]. [74] also reported in a study of 50 patients with bronchiectasis that nearly 50% of inhaled steroid users with bronchiectasis had evidence of adrenal suppression and that this correlated with poorer health status. a large improvement in quality of life using the SGRQ was noted (mean difference −10. chest pain (19 versus 0%.9% had bronchospasm requiring bronchodilator treatment.17) log10 cfu·mL−1. they may reduce systemic absorption and side effects and perhaps reduce collateral damage. demonstrated reduced sputum purulence. aeruginosa at baseline were negative at follow-up. in a pre-specified analysis based on patients that took >80% of the doses.8% of patients colonised with other pathogens were negative by quantitative sputum culture at the end of treatment. aeruginosa colonisation in the UK. however.1183/09031936. testing nebulised β-lactams. Aztreonam is an inhaled antibiotic licensed for treatment in cystic fibrosis.D. Tolerance was generally better with this dose of gentamicin compared with the previous tobramycin study. Trial evidence has been mixed. such as tobramycin. intolerance was a major issue.00119114 7 .0001) [82]. and 92.11). Four out of 13 patients colonised with P. consideration of potential adverse events associated with combined ICS-LABA [71. for example through resistance development in gastrointestinal microorganisms [75]. It is recommended to administer the initial dose in a controlled setting like an outpatient department to detect bronchospasm prior to starting home treatment [2]. [83] studied nebulised colistin delivered via the I-Neb (Philips Respironics.1) dyspnoea (32% versus 8%.96 (1. but two such trials have been recently reported. p=0. Increased cough (41 versus 24%. 27 (20%) out of 134 of aztreonam-treated patients discontinued DOI: 10. and excluded smokers and patients receiving other long term antibiotics. Two recent phase III trials in bronchiectasis randomised 266 (AIR-BX1) and 274 (AIR-BX2) patients to aztreonam or placebo over the course of two 28-day treatment cycles (with 28 days off treatment between cycles) [84]. quality of life. Until recently.34–8. No nephrotoxicity or ototoxicity was reported [82]. and the study narrowly failed to meet this end-point (colistin group 165 days versus placebo 111 days. p=0. p=0. although 21.006).67 (7. MANAGEMENT OF BRONCHIECTASIS IN ADULTS | J. Unfortunately. two exacerbations in the previous year and an FEV1 >30%. similar to the previous experience with tobramycin. nebulised tobramycin significantly reduced the primary outcome of P. the first disease specific instrument to be developed [85]. There is no role for oral corticosteroids in bronchiectasis outwith the treatment of ABPA or for acute exacerbations of bronchiectasis that are accompanied by wheezing suggestive of concomitant asthma [2]. there have been little supporting data with clinically important end-points. HAWORTH et al. Gentamicin has been used widely in the UK following the publication of this trial. p<0. Inhaled antibiotics reduce airway bacterial load and recent data clearly demonstrate that reductions in bacterial load are associated with reduced airway inflammation. however. Commonly used agents in clinical practice are primarily those used to target P. and most have been extrapolated from the CF population in which inhaled antibiotics suppress bacterial load. p<0. In an early phase II double-blind placebo-controlled study by BARKER et al. Currently. no inhaled antibiotic agents are approved for use in bronchiectasis by any regulatory agency either in Europe or North America. The primary outcome was the newly developed Quality of Life Bronchiectasis (QOL-B) questionnaire. p=0. reduce exacerbations and hospital admissions [77]. Holme et al. 72]. In the secondary end-points. Until recently there is a lack of large phase III trials of inhaled antibiotics. providing theoretical rationale for clinical use of inhaled antibiotics [76]. p=0. Several open label studies in the late 1980’s. Russia and Ukraine [83]. Subsequently a single-blind randomised controlled trial of nebulised gentamicin for 12 months reported significant benefits [82]. as measured by the SGRQ and LCQ. After 12 months there was a significant reduction in bacterial density in the gentamicin group (2. Chichester. In addition. This trial recruited 144 patients with chronic P.01) and wheeze (16 versus 0%. 27 patients were randomised to gentamicin 80 mg twice daily and 30 patients to 0. Inhaled antibiotics Inhaled antibiotics have theoretical advantages over oral therapies by delivering higher concentrations of drug to the airway.0001) [47]. Whether this same risk applies to patients with bronchiectasis is unclear and requires further study. a statistically significant difference in time to first exacerbation was seen [83].5 per year in the placebo group compared with 0 per year in the gentamicin group. The primary outcome was the time to next exacerbation. aeruginosa bacterial load but was poorly tolerated by some patients . This phase II study has therefore never been followed by a larger phase III trial [81]. aeruginosa. CHALMERS ET AL.9% saline twice daily. was improved and exacerbations were reduced (median 1. The study enrolled patients with chronic bacterial colonisation (three positive sputum cultures in the past 12 months). only two patients were withdrawn for this reason.01) were reported in the tobramycin group (table 2).01).

discontinuation.5 in resistant isolates gentamicin. Aztreonam [84] AIR-BX1: A: 134. 2× phase III QOL-B Two 28 day Positive sputum for P. not on long-term scores. in both studies). improved bronchoconstriction controlled trial following 12 months) and within SGRQ (mean difference leading to exacerbation) 21 days of completing −10.6 (1. versus 6%. tobramycin in 4/36.56 versus 5%.00119114 P: 132. randomised pathogens in at least three bacterial load at 12 months two withdrawals. controlled trial sputum samples in the (2.8 MANAGEMENT OF BRONCHIECTASIS IN ADULTS | J.11).006). AIR-BX2: double-blind questionnaire treatment aeruginosa or other week 4 (mean difference 0. No difference in QOL-B at AIR-BX1 adverse events DOI: 10. p<0.1–4. 5 (80) studies following purulence 4 months/ with purulent sputum that reduced neutrophil elastase failure of oral 16 weeks failed to clear following activity .01).56 log10 cfu·mL−1. bacterial load treatment patients. p<0.67 log10 cfu·mL−1.influenzae) AIR-BX1 and 4. exacerbation.0001). Continued . exsmokers of improved SGRQ and LCQ >1 year. placebo developed randomised withdrawn positive cultures in 111 days. 1. Bronchiectasis patients Reduced sputum purulence.1183/09031936.D.8 leading to A: 136. 13/37 cleared P. reduction in required dose reduction previous year.1–8. p=0. Three open label Sputum Continuous. detected. P: 71 Phase III Time to first 6 months P. inflammation. Colistin [83] A: 73. two 7. gentamicin levels exacerbations in the p<0. AIR-BX2- 28 day off FEV1 >20% predicted. Gentamicin [82] A: 27.011) in AIR-BX2).9%. improved PEFR. Increased dyspnoea. P: 30 Single-blind Bacterial load 12 months Patients colonised with any Significant difference in Bronchospasm in 21. reduced sputum antibiotics oral amoxicillin volume.] n Current phase Primary Duration Patient population Main results Safety of development outcome Amoxicillin [78–80] 6 (78). no difference in time to first exacerbation. P: 138 randomised score at week 4 courses with Gram-negative organisms (95% CI −3. TABLE 2 Current state of development of inhaled antibiotic agents for non-cystic fibrosis bronchiectasis Agent [ref. FEV1 mean difference new resistance to 8 weeks) 56 versus 53% 4. No issues identified. CHALMERS ET AL. aeruginosa-colonised Missed primary end-point Five patients (7%) double-blind exacerbation (patients patients (two or more (colistin 165 days. predicted. taking >80% of doses. mean age 66 aeruginosa load (mean chest pain and wheezing.5 points. reduced airway antibiotics. able to exacerbations (median 0 in in one patient.0001). p=0. aeruginosa-colonised Significant reduction in P. FEV1 >30% the saline group.2.41. aeruginosa from sputum. Tobramycin [81] A: 37. p=0. difference in QOL-B in both to discontinuation: 10 studies at week 12 (p=0. no tolerate test dose of the gentamicin group.96 log10 cfu·mL−1 versus elevated serum preceding 12 months.7. no antipseudomonal improved time to first resistant strains at antibiotics for an exacerbation in patients follow-up. 3 (79). (total duration versus 63 years. P: 37 Phase II study P.7) in discontinuation: 22 controlled trial alternating (excluding H. p=0. aeruginosa 28 days P. p=0. no significant change in FEV1. no adverse events leading treatment chronic sputum production.

FEV1: forced expiratory volume in 1 s. Liposomal A: 20. MIC: minimum inhibitory concentration.D. no hospitalisation).89.2 versus in minimal inhibitory randomised treatment cycle treatment in previous 12 months. p=0. no significant difference in SGRQ (mean difference −3. QOL-B: quality of life bronchiectasis questionnaire. no significant ciprofloxacin group.027). LCQ: Leicester Cough Questionnaire. reduced number of ciprofloxacin at day 28.04–0. p=0. >2 exacerbations bacterial load −4.059).6). P: 64 Phase II double Bacterial load 28 days Idopathic or post-infective Mean difference in bacterial 10% of patients [86] blind treatment with bronchiectasis. microorganisms. positive for target (36. able to differences in proportion of difference in adverse produce sputum. PEFR: peak expiratory low rate. Georges Respiratory Questionnaire. −0. 95% CI 0.001. A: active.62 log10 cfu·mL−1 developed resistance randomised follow-up to more exacerbations in the versus −0.DOI: 10. two or load −3.27 log10 cfu·mL−1.] n Current phase Primary Duration Patient population Main results Safety of development outcome Ciprofloxacin DPI A: 60. MANAGEMENT OF BRONCHIECTASIS IN ADULTS | J. DPI: dry powder for inhalation.046). concentrations to controlled trial with intervening cycles) p=0. p=0. P: placebo.7 versus 39.1183/09031936. aeruginosa No significant difference ciprofloxacin [87] double blind after first 28-day (three 28 day patients. CHALMERS ET AL.002. 28-day off exacerbations in the active no increase in adverse periods) treatment group (OR 0. P: 22 Phase II study Bacterial load 24 weeks P. (MIC >4 mg·L−1) in the controlled trial 84 days previous 12 months (one p<0.2 events.1%.00119114 TABLE 2 Continued Agent [ref.56. cfu: colony forming units. 9 . aeruginosa-colonised Reduction in P. culture patients with exacerbations events between groups. aeruginosa: Pseudomonas aeruginosa. P. median time to pulmonary exacerbations reduced in the per protocol population (p=0. SGRQ: St.08 log10 cfu·mL−1.

Eradication Although there is no evidence to support eradication per se. There are limited long-term outcome data for bronchiectasis patients after surgery and one of 10 DOI: 10. not the end for inhaled antibiotics in bronchiectasis. While effective in suppressing airway bacterial load. although in highly localised bronchiectasis with symptoms that cannot be controlled by maximal medical therapy. microbiology and severity may have contributed. The current evidence for inhaled antibiotics in bronchiectasis is summarised in table 2. are substantial and impact on compliance. This agent aims to improve tolerability by liposomal encapsulation of the drug. The primary outcome was not reached. Several reasons for the failure of this treatment to translate into bronchiectasis can be speculated. CHALMERS ET AL. These negative trials are. cough. reducing the amount of free drug in contact with the pulmonary epithelium. the trials to date illustrate some of the issues with inhaled antibiotics in bronchiectasis. Such data are not available to suggest if shorter durations are equally effective [92]. the dose used was optimised for CF rather than bronchiectasis and future studies should consider specific dose-ranging studies in bronchiectasis. but consensus guidelines recommend 14 days of treatment with antibiotic therapy guided by previous sputum microbiology [2]. while most other trials have limited their indication to patients with chronic P. The only real published data are from an inpatient intravenous antibiotic study in which MURRAY et al. aeruginosa cfu·mL−1 in the treatment arm (20 for ciprofloxacin versus 22 for placebo) over 24 weeks. Treating exacerbations The appropriate length of treatment for exacerbations is not known. The treatment burden associated with nebulised therapies. the heterogeneity of the population in terms of aetiology. phase 3 trials of two formulations of inhaled ciprofloxacin have now commenced [86. chest discomfort) and development of resistant organisms. MCCULLOUGH et al. 87].046 in the per protocol population) In contrast to the previous experience with aminoglycosides and aztreonam. throat irritation or pain. however. Therefore. There is a great need for prospective data on the management of bronchiectasis exacerbations. aeruginosa [86]. This is the case for the dual release liposomal ciprofloxacin preparation. Worsening of dyspnoea and cough were the major drivers of intolerance. As of 2014. p=0. 9. treatment in AIR-BX1 (versus 4 (3%) out of 132 treated with placebo). Surgery Surgery is now rarely employed in bronchiectasis. Retrospective studies reporting high rates of P. There was also a reduction in time to next exacerbation (median 134 days versus 58 days. aeruginosa and other bacteria. First. and secondary end-points such as exacerbations were also negative [84]. without any significant differences in exacerbations [86] These trials have included patients with both P.MANAGEMENT OF BRONCHIECTASIS IN ADULTS | J. aeruginosa occurs frequently in bronchiectasis both in clinical practice and in the placebo arms of randomized controlled trials [90. medication-related adverse effects (e. In a phase II study (n=60 patients for ciprofloxacin and n=64 patients for placebo) ciprofloxacin was associated with a significant reduction in bacterial load during a 28-day treatment period.1183/09031936. most specialist bronchiectasis centres will attempt eradication of P. In keeping with recommendations in cystic fibrosis. [92] demonstrated significant reductions in 24-h sputum volume and C-reactive protein. referral for lobectomy or segmentectomy may be considered.00119114 . Finally. abnormal taste sensation. 87]. 89]. however. The phase II study showed excellent results with a significant reduction in P. A dry powder inhaled formulation has the potential to significantly reduce treatment burden. Patients treated with inhaled antibiotics should be assessed for adherence. both the dry powder and liposomal ciprofloxacin preparations were well tolerated [86. which may have contributed to previous intolerance of aminoglycosides. aeruginosa eradication with treatment must be interpreted in light of data that suggests spontaneous clearance of P. aeruginosa persistence as an independent mortality predictor in addition to being associated with more extensive lung disease and worse pulmonary function [7. Therefore the authors will typically perform a second sputum sample pre-treatment before commencing eradication [2] The BTS guidelines provides a useful algorithm for P. Slow release of the drug from liposomes allows for once-daily dosing which may also aid compliance [87].D. with improvements in quality of life. aeruginosa upon first isolation [2]. which include both the time to administer the dose and also to care for the machinery. and 10 (7%) out of 135 stopped active treatment in AIR-BX2 (versus 5 (4%) out of 137 treated with placebo). There were imbalances in the groups in AIR-BX1 in terms of the frequency of COPD and some markers of severity which may be relevant when considering respiratory tolerance [84]. [88] assessed compliance in 75 patients with bronchiectasis and found self-reported adherence of 52% for inhaled antibiotics and 39% for airway clearance .g. some antibiotic agents appear to have important problems with tolerability. exercise capacity and clearance of bacteria after 14 days of treatment . all of the prognostic studies to date have clearly identified P. 91]. aeruginosa eradication [2].

the bronchiectasis severity index (BSI). including exacerbations and impaired quality of life. and can have serious side effects for both the patient.5 2 ⩾18. These disorders also need to be recognised and managed. DOI: 10. Severity ranges from patients without daily symptoms who have infrequent exacerbations. The authors have created an online calculation tool accessible at www. 5–8 points: moderate risk of hospitalisation and mortality. 99]). patients require treatment appropriate to their stage and severity of disease. Management of co-morbidities Patients with bronchiectasis are frequently elderly. derived a scoring system. Italy and Belgium. Recently. Treatments can place a large burden on patients in terms of time. Rate of lung function decline is highly variable and is associated with P.1183/09031936. 94]. and it is important to manage associated cardiovascular disease and other co-morbidities. aeruginosa colonisation and severe exacerbations [98. the European bronchiectasis network described the first clinical prediction tool for hospital admissions and mortality in bronchiectasis [7].com and the scoring system is shown in table 3.5 0 FEV1 % predicted >80 0 50–80 1 30–49 2 <30 3 Hospital admissions in the past 2 years Yes 5 No 0 Exacerbation frequency in the past 12 months 0–2 0 ⩾3 2 MRC dyspnea score 1–3 0 4 2 5 3 Bacterial colonisation Pseudomonas aeruginosa 3 Other PPMs 1 None 0 Radiological severity ⩾3 lobes involved or cystic bronchiectasis 1 <3 lobes involved 0 0–4 points: low risk of hospitalisation and mortality. ⩾9 points: high risk of hospitalisation and mortality. and for the community in terms of antibiotic resistance [100]. Therefore. This study. CHALMERS ET AL. to patients requiring lung transplantation.bronchiectasisseverity. Anxiety and depression are very common in bronchiectasis with a reported prevalence of anxiety of 18–55% and of depression of 13–34% [95–97]. the largest series described an operative complication rate of 8. This is the only prediction tool or severity classification system for bronchiectasis that TABLE 3 The Bronchiectasis Severity Index Domain Points Age years <50 0 50–69 2 70–79 4 ⩾80 6 Body mass index kg·m-2 <18. MANAGEMENT OF BRONCHIECTASIS IN ADULTS | J. conducted in the UK. which can accurately identify patients at the highest risk of complications.D.00119114 11 . A stepwise approach to treatment Bronchiectasis is a heterogeneous disease with a highly variable impact on patients.9% for thoracoscopic lobectomy or segmentectomy for bronchiectasis [93.

102].00119114 . neutrophilic inflammation. The authors would advocate a stepwise approach to management of bronchiectasis similar to that used in asthma and COPD [101.MANAGEMENT OF BRONCHIECTASIS IN ADULTS | J. Severity of disease and risk of complications provides a useful framework for clinical decision making around which patients require long-term treatments such as macrolides. exacerbation frequency or the presence of P. surgery Airway clearance General management (applies at all stages of disease: Vaccination against influenza and pneumococcus Inhaled corticosteroids in techniques selected patients Manage co-morbidities and underlying cause Long-term antibiotic Pulmonary rehabilitation therapy Prompt treatment of exacerbations Macrolides for patients with Sputum surveillance of Pseudomonas aeruginosa and frequent exacerbations Anti-inflammatory non-tuberculous Mycobacteria Inhaled antibiotics particular with therapy Pseudomonas aeruginosa colonisation Therapies in advanced disease Regular physiotherapy±adjuncts Inhaled corticosteroids in (devices/hyperosmolar agents) selected patients Consider macrolides for patients Severe bronchiectasis or persistent with frequent exacerbations symptoms despite standard care Regular physiotherapy±adjuncts (devices/hyperosmolar agents) Moderate severity or persistent symptoms despite standard care Daily physiotherapy Mild severity FIGURE 2 The stepwise management of non-CF bronchiectasis. A look to the future: new therapies The above highlights the difficulties of treating bronchiectasis. 12 DOI: 10. CHALMERS ET AL. Alternative oral antibiotics such as β-lactams or tetracyclines may be appropriate for patients intolerant or not suitable for macrolides. Phase II studies of oral neutrophil elastase inhibitors have been reported while others are ongoing [105]. A model flow chart based on the authors own practice is presented in figure 2. has been largely resistant to existing treatments [103]. Patients with bronchiectasis should be commenced on therapy at a stage appropriate to their severity of disease which should be based on clinical judgement and may be augmented by assessment of clinical severity parameters such as the BSI. 107]. Given the previously noted importance of neutrophil elastase in pathogenesis [104]. current therapies that are labour intensive and are associated with adverse effects. 107]. The predictors described in table 3 were independently identified by a large Spanish study [89] which adds to the external validity of both studies. Patients who continue to have persistent symptoms or exacerbations despite treatment at stage 1 should have their therapy escalated and so on. with a limited number of options. In addition.D. has so far undergone external validation. airway adjuncts. CXCR2 is expressed on a number of leukocytes but most prominently on neutrophils [106. An absence of large randomised trials has meant that there are no licensed therapies for bronchiectasis in Europe or FDA-approved therapies in the USA. Data show the ability to inhibit elastase activity but without clear clinical benefits yet. inhaled antibiotics and other measures. It is a key neutrophil trafficking receptor during inflammation. This represents a pragmatic approach to treatment decisions that reflects how the majority of physicians practice. which is central to the pathogenesis of bronchiectasis. CXCR2 antagonism is likely to reduce rather than prevent neutrophil recruitment to the Long-term oxygen therapy. It also has diverse effects on inflammation as CXCR2 blockage inhibits mucus secretion both by inhibiting neutrophil recruitment and through direct inhibition of goblet cells [106.1183/09031936. this represents a promising therapeutic target. Much of the development of novel agents centres around targeting neutrophilic inflammation. lung transplantation. aeruginosa.

00119114 13 . Statins have immunomodulatory effects and may have a role in neutrophilic inflammation. A second trial in patients with P. The developing landscape in bronchiectasis necessitates collaborative working to facilitate multinational clinical trials.bronchiectasis. New therapies under development are shown in figure 3. the ECFS clinical trials network and the ECFS patient registry [115]. aeruginosa will shortly be reported. the study reported higher airway inflammation despite reduced neutrophils and an increase in discontinuation due to infections [108]. Towards these goals a number of countries are now establishing national registries for bronchiectasis. Multiple new therapies are in development for cystic fibrosis that specifically target Cystic fibrosis transmembrane conductance regulator (CFTR) function [114] Whether these will find a role in non-CF bronchiectasis is unclear where the role of CFTR mutations are controversial. DOI: 10. CFTR: cystic fibrosis transmembrane conductance regular. Advances in mucolytic. as occurred in a previous trial of a leukotriene B4 receptor antagonist in cystic fibrosis [109. CHALMERS ET AL. A new anti-pseudomonal compound based on the antimicrobial peptide protegrin is currently in proof of concept trials for patients with exacerbations [112] and several new specific anti-pseudomonal antimicrobials are currently in development [113]. This study found improved cough in statin users. airway as other chemoattractants. Phase II studies of CXCR2 antagonists in bronchiectasis have been reported in abstract form. with one (AZD5069) reducing sputum neutrophil counts by 69% versus placebo (26 patients in each group) [108]. The future for bronchiectasis patients is bright. MANAGEMENT OF BRONCHIECTASIS IN ADULTS | J.D. Conclusions The goals of treatment in bronchiectasis are to facilitate airway clearance. if momentum can be sustained to produce the treatments and the evidence we need to provide high quality care. suppress bacterial infection and prevent exacerbations.eu). but statin use was also associated with an increase in adverse events [111]. including in the USA through the US COPD Foundation [116]. A look to the future: national and international networks Cystic fibrosis research has benefitted greatly from the creation of national and international networks such as the European Cystic Fibrosis Society (ECFS). antibiotic and anti-inflammatory therapies are urgently Inhaled amikacin Circulating neutrophils Pulmonary Airway neutrophil epithelium Inhaled colistin CXCR2 antagonists Novel specific anti-pseudomonals Pseudomonas aeruginosa Inhaled ciprofloxacin Neutrophil elastase Haemophilus influenzae inhibitors Mannitol Statins CFTR-specific therapies FIGURE 3 New therapies in development for bronchiectasis and their possible role. is working to bring together clinical researchers in Europe by creating a European bronchiectasis registry. the EMBARC network (www. Novel antimicrobials are needed in the face of rising antibiotic resistance.1183/09031936. Atorvastatin was recently the subject of small RCT in patients with moderate bronchiectasis [111]. improve quality of care for bronchiectasis patients and support translational science. particularly leukotriene B4 have been shown to be elevated in bronchiectasis and to drive neutrophil recruitment [13]. Interestingly. and in Europe through the European Respiratory Society. One concern regarding anti-inflammatory drugs has been the potential that reducing neutrophil numbers could lead to uncontrolled bacterial infection. 110].

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